This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. One of the major challenges for CMV vaccine development is the fact that CMV establishes secondary persistent infections in CMV-immune individuals despite the presence of significant antibody and T cell responses. We recently demonstrated that super-infection by CMV is enabled by the viral US2-11 glycoproteins -US2, US3, US6 and US11- all of which inhibit antigen presentation by major histocompatibility complex class I (MHC-I) to CD8+ T cells. These observations suggest that CMV lacking the US2-11 region can be used to monitor whether a CMV-specific CD8+ T cell response is "protective", i.e., able to control primary viremia as observed for sero-positive individuals. A goal of this proposal is therefore to define the CD8+ T cell response required for protection against US2-11-deleted virus and to correlate these results with protection against primary infection with wildtype virus. A further goal is to determine the contribution of each individual immunevasin encoded in the US2-11 region in promoting super-infection. This work will challenge existing paradigms, specifically the assumptions that live CMV vaccines need to be based on replicating CMV and that single subunit vaccines confer protective T cell responses. We further anticipate to develop new and improved ways to test CMV vaccines and to improve CMV-based vectors. Therefore, we believe that our research will have a significant and lasting impact on the development of CMV vaccines and CMV-based vaccine vectors.